The present invention relates to thixotropic pharmaceutical or veterinary, dietary or cosmetic compositions containing one or more active substances intended for filling capsules with a hard casing, called hard capsules, at room temperature.
The term xe2x80x9croom temperaturexe2x80x9d is understood to mean a temperature substantially between 15 and 30xc2x0 C.
Two types of capsules are used for medicinal products intended for oral, rectal or vaginal administration, namely capsules with a soft case and capsules with a hard case.
Individual liquid or pasty pharmaceutical compositions are conventionally presented in soft capsules. However, the process for manufacturing soft capsules requires the use of complex plants and specialized custom molders, so that the use of hard capsules may, for economic reasons, be preferred.
Hard capsules are conventionally used for packaging solid substances such as powders and granules. In some cases, filling hard capsules with solid substances poses certain technical problems such as, on the one hand, the generation of contaminating dust when handling active and toxic substances (anticancers, hormones)xe2x80x94something which may prove to be particularly dangerousxe2x80x94and, on the other hand, the nonuniform filling from one hard capsule to another when the active substance or substances are lightly dosed.
This is why a solid active substance may be combined with a liquid vehicle before being packaged in hard capsules (US H 672).
The use of a liquid vehicle for the filling of hard capsules also raises problems, since the liquid can flow out between the body and the top of the hard capsule. Leaks are generally avoided by sealing the hard capsules (EP 488 181 and WO-91/02520). This sealing operation requires a particular know-how and an additional step incurring a not insignificant additional cost.
An alternative to sealing the hard capsules has been proposed. It consists in filling the hard capsules with a composition containing the active principle in the dissolved or dispersed state. This same composition is liquid or pasty and of low viscosity during the filling and it then thickens inside the hard capsules.
According to a first filling mode, called xe2x80x9chot fillingxe2x80x9d, the composition, which is pasty at room temperature, is thinned by heating (EP-49 909). This method cannot be applied to heat-sensitive active principles such as certain anticancer agents, vitamins and antibiotics.
According to a second filling mode, called xe2x80x9croom-temperature fillingxe2x80x9d, GB-1 590 864 provides compositions such that
their viscosity at 20xc2x11xc2x0 C. is between 500 and 5000 mpa.s, preferably between 1000 and 3000 mPa.s, measured at 450 revolutions per minute on a Haake viscosimeter,
and such that
their surface tension is greater than 20 dynes/cm, preferably greater than 30 dynes/cm.
However, GB-1 590 864 does not specify what the viscosity of the compositions at rest must be.
Moreover, a third filling mode, combining the first two, has been described in EP-49 909. According to this method, a shear-thinning composition, containing liquid paraffin, hydrogenated castor oil and colloidal silica, is heated to 40xc2x0 C.
The Applicant has demonstrated that the shear-thinning nature of the compositions for filling hard capsules of the prior art, although necessary for ensuring proper filling of the hard capsule, nevertheless proves to be insufficient.
This is because it is also imperative to check that the formulation at rest in the hard capsule restructures sufficiently strongly and above all sufficiently quickly, after filling, to avoid any leakage between the two parts of the hard capsule.
It is therefore absolutely essential for the consistency of the composition at rest to be sufficient to avoid any flow of the composition between the two parts of the hard capsule.
Among the raw materials that are used in conventional filling compositions are polyethylene glycols. Polyethylene glycols are intended to dissolve the water-soluble active principle of the filling composition, by virtue of their hydrophilic properties (EP-276 116, EP-488 181 and EP-49 909).
It has been found that the incorporation, as continuous phase, of polyethylene glycols, and more particularly of polyethylene glycols of low average molecular masses, in the filling composition may pose serious physicochemical interaction problems and therefore stability problems.
In particular, these polyethylene glycols are hygroscopic and attract water from the gelatin into the continuous phase making the case brittle and weak during storage.
The filling compositions of the present invention are advantageously free of any polyethylene glycol, and in particular of polyethylene glycol of low average molecular mass, which would run the risk of weakening the case of the hard capsules.
The objective of the present invention is to provide compositions termed xe2x80x9cthixotropicxe2x80x9d compositions containing one or more active substances which allow any filling of the hard capsules at room temperature and which ensure the absence of leaks between the two parts of the hard capsule without it being necessary to make use of the sealing usually recommended for this type of pharmaceutical dosage form.
The rheological properties of the formulations of the invention ensure effective filling at room temperature and the absence of leaks from the filled hard capsules.
It will be recalled that a liquid or pasty thixotropic composition has a shear-thinning character which is manifested by a reduction in the apparent viscosity under the effect of increasing shear. Furthermore, any variation in the shear conditions causes a structural modification delayed over time. Thus, in particular a gradual, total or partial recovery in consistency is observed after the shear has stopped.
The rheological parameters chosen as being particularly representative of the consistency of the formulations are:
the complex modulus G*, the value of which is greater the thicker the product under study, which complex modulus is a synthesis of the elastic and viscous properties of the material, and
the phase shift xcex4, of between 0xc2x0 and 90xc2x0, knowing that a phase shift of greater than 45xc2x0 characterizes a predominantly viscous nature and, conversely, a phase shift of less than 45xc2x0 demonstrates a predominantly elastic nature characteristic of a structured material.
The present invention relates to liquid or pasty thixotropic compositions containing one or more active substances, intended for filling hard capsules at room temperature, such that:
their complex modulus G* is greater than about 100 Pa,
their phase shift xcex4 is less than about 45xc2x0,
their viscosity decreases with increasing shear rate,
under the effect of a constant shear rate xcex30, the viscosity of the said compositions decreases in a delayed manner over time and stabilizes at the equilibrium value xcex7eq of between 10 mPa.s and about 10 000 mPa.s, when xcex30 is between 100 and 1000 sxe2x88x921 and
after making the said shear rate 0, the complex modulus and the phase shift of the said compositions resume, after a time t of less than 1 hour, G* and xcex4 values of greater than about 100 Pa and of less than about 45xc2x0, respectively.
The compositions according to the invention are therefore defined, on the one hand, by their shear-thinning nature, that is to say that their viscosity decreases when the intensity of the shear increases and, on the other hand, by the decrease in their viscosity over time for a given shear.
The formations of the invention thus thin in the hard-capsule filling machine due to the effect of the shear induced by the agitation present from the feed hopper right to the dispensing nozzle. This property makes it particular easy to fill the hard capsules.
For each shear rate, the viscosity of the compositions of the invention decreases over time and finally stabilizes at an equilibrium value denoted xcex7eq. The compositions according to the invention have equilibrium viscosities xcex7eq at 100 sxe2x88x921 and 1000 sxe2x88x921 of between 10 mPa.s and 10 000 mPa.s, preferably between 100 mPa.s and 1500 mPa.s. It is entirely unnecessary to make use of a heating operation, as required in certain processes of the prior art (U.S. Pat. No. 4,450,877).
The compositions according to the invention are also defined by a significant recovery in consistency delayed over time.
The compositions of the invention, thinned in the hard-capsule filling machine, resume their initial consistency after a sufficient rest time, so as to avoid any risk of a leak from the full capsule.
The formulations according to the invention are characterized by G* values of greater than 100 Pa, preferably greater than 1000 Pa, and/or xcex4 values of less than 45xc2x0, preferably less than 25xc2x0, and/or a recovery time t of less than 1 hour and preferably less than 30 minutes, and/or xcex7eq values of between 100 mPa.s and 1500 mPa.s when the shear rate is between 100 and 1000 sxe2x88x921.
Once the recovery has been completed, G*eq is greater than 100 Pa, preferably 1000 Pa, and xcex4eq is less than 45xc2x0, preferably less than 25xc2x0.
The hard capsules used within the context of the present invention consist of gelatin, of a cellulose polymer (such as hydroxypropylmethyl cellulose) or of any other polymer capable of fulfilling the use functions of gelatin in the form of a hard capsule.
According to a preferred embodiment, the thixotropic compositions of the present invention are dispersions containing a continuous liquid or pasty dispersing phase, a viscosity-modulating dispersed phase in the particulate or micellar state and at least one active substance present in the dissolved and/or dispersed state.
The dispersing phases of the invention are characterized by their wide polarity range in terms of hydrophilic-lipophilic balance (HLB). The raw materials used in the formulation of these dispersing phases of the invention have hydrophilic, lipophilic or amphiphilic properties of variable HLB which allow the dissolution of dispersion of liquid and solid active principles which are themselves hydrophilic, lipophilic or amphiphilic.
The continuous phase of these compositions advantageously consists of at least one vehicle such as oils, their derivatives, and more particularly amphiphilic esters having an HLB of between 3 and 15, such as amphiphilic polyglycolized glycerides, like LABRASOL(copyright) and LABRAFIL(copyright) sold by Gattefosse.
The use of amphiphilic vehicles having a hydrophilic tendency represents a good alternative to the hydrophilic polyethylene glycols of the prior art. Apart from polyethylene glycols, the products conventionally used in the formulation of liquid or pasty thixotropic preparations for a hard capsule are rather lipophilic (GB-1 590 864, U.S. Pat. No. 4,450,877, US-H672, EP-461 290).
The amphiphilic continuous phases having a hydrophilic tendency used within the context of the present invention, unlike the excipients of the prior art, prove to be ideally suited to hydrophilic, lipophilic or amphiphilic active principles, whether they dissolve or disperse respectively.
The viscosity-modulating dispersed phase of the compositions according to the invention may be chosen from hydrophilic or hydrophobic pyrogenic silica particles, the mean size of which may be between 5 and 50 nm, preferably between 7 and 20 nm, and the specific surface area between 10 and 450 m2/g, preferably between 70 and 410 m2/g, such as AEROSIL(copyright) sold by Degussa, and ethylene oxide and propylene oxide copolymers, such as SYNPERONIC(copyright) products sold by ICI, and mixtures thereof.
The dispersed phase combined with the continuous phase makes it possible to achieve HLB values ranging up to about 20.
The viscosity-modulating dispersed phase of the compositions according to the invention preferably represents from 1 to 30% m/m, more preferably from 5 to 15% m/m, of the preparation.
The excipients used in the formulation of the thixotropic compositions according to the invention are chosen from pharmaceutically acceptable excipients that are inert with respect to the active substances that it is desired to formulate.
Furthermore, these excipients are chosen from excipients that are compatible with the casing of the hard capsules.
The excipients which are used in the formulation of the thixotropic compositions according to the invention are advantageously endowed with hydrophilic, lipophilic or amphiphilic properties with, for these, a variable hydrophilic-lipophilic balance (HLB), which allow the dissolution or dispersion of both hydrophilic and lipophilic active substances. The HLB of the vehicles may vary from 4xc2x11 for a combination of LABRAFIL(copyright) M1944CS and AEROSIL(copyright) to 20xc2x11 for a combination of LABRASOL(copyright) and SYNPERONIC(copyright).
The compositions according to the invention contain an active substance which may be liquid or pasty but also solid, for example milnacipran hydrochloride (solubility in water of 600 g/l), baquimast (solubility in water of 0.23 g/l), nifedipine, triamterene, aluminum hydroxychloride, sodium salicylate, vancomycin, paramethadone and griseofulvin.
The hard capsules used within the context of the present invention consist of gelatin or of any cellulose polymer capable of fulfilling the functions of the use of gelatin in the form of a hard capsule, such as hydropropylmethyl cellulose.
The invention is not limited to these examples and a person skilled in the art will be easily able to include any active substance of his choice, whether liquid, pasty or even solid, in the compositions described.
The present invention also relates to the use of the compositions described above in a cosmetic, dietary, pharmaceutical or veterinary preparation.